Pharmaceutical formulation consisting of a plant dry extract with a calcium coating

ABSTRACT

Pharmaceutical formulation, its use, and method for its manufacture The present invention relates to a pharmaceutical formulation of a calcium salt and a dry plant extract in the form of a coated tablet, wherein it has a core of at least one dry plant extract, enveloped by at least one coating of at least one calcium salt. The plant extracts for the core may be selected from:  Vitex agnus castus  (chaste tree);  Belamcanda chinensis  (leopard lily);  Cimicifuga racemosa  (black cohosh);  Trifolium pratense L . (purple trefoil);  Oenothera biennis hom . (primrose);  Glycine soja  (soy bean);  Serenoa repens  (saw-palmetto);  Urtica dioica  (stinging nettle), in particular its root;  Cucurbita pepo  (pumpkin), in particular its seed;  Pygeum africanum ; as well as suitable mixtures of these.

FIELD OF THE INVENTION

[0001] The present invention relates to a pharmaceutical formulation inaccordance with the preamble of claim 1, a use thereof in accordancewith claim 11, and a method for its manufacture in accordance with claim13.

BACKGROUND TO THE INVENTION

[0002] 17β-estradiol, which is naturally formed in the ovaries [alsoreferred to as E₂], has a general proliferation-enhancing action inhumans and animals. In addition to controlling the female cycle, it has,i.a., a homeostatic effect on the metabolism of the bone, while alsopreventing the formation of atherotic plaques on vessel endothelia.

[0003] During menopause, estradiol levels decrease due to cessation ofovarial function. In the absence of sufficiently high estradiol levelsin the blood, the activity of the osteoclasts, and thus breakdown of thebone mass—so-called “osteoporosis”—predominates in the bone tissue,which is accompanied by an increased risk of skeletal breakage.

[0004] In recent times it was found that this syndrome of osteoporosisbrought about by lack of sexual hormone is not restricted to women, butthat from a certain advanced age, osteoporosis brought about by lack ofsexual hormone also occurs in men, in particular in connection withailments of the prostate.

[0005] The classical prophylaxis and therapy in woman consists insupplementing natural estrogen by administration of natural andsynthetic estrogens. In particular, for prophylactic purposes, calciumdoses of approx. 1 gram of calcium per day are applied in man and woman.

[0006] Administration of estrogens such as, e.g., 17β-estradiol or thechemical derivatives thereof is, however, accompanied by the known graveside effects of uterotrophic effect, increased risk of thrombo-embolism,weight gain, and the like.

[0007] There have been many attempts reported in the prior art to findmedicaments capable of producing an estrogen-type effect either withoutundesireable side effects, or with strongly diminished undesirable sideeffects. Plant extracts have been frequently used that exhibit thedesired action of osteoporosis prophylaxis, but not, however, theundesirable uterotrophic effects.

[0008] Thus, for example, WO 99/47149 (=EP 1064009A1) to the presentapplicant discloses that extracts from iridaceae, in particular fromCimicifuga racemosa and Belamcanda chinensis and of the isoflavonoidtectorigenin contained therein, do not have an estrogen-type effect onthe uterus, yet do so in the hypothalamo-hypophysary axis, in thecardiovascular system, and in the bone, so that these plant extracts maybe employed for the prophylaxis and therapy of osteoporosis.

[0009] Moreover, calcium preparations for the prophylaxis ofosteoporosis are known in the prior art. A pharmaceutical formulation tothis end, besides an injection solution, is preferably an effervescenttablet for oral application. Such effervescent tablets may, e.g., havethe following composition:

[0010] Tablets with 500 mg of Ca2+: 1250 mg of calcium carbonate, 2050mg of citric acid, further constituents: lactose 1H2O, macrogol 6000,Povidon, sodium cyclamate, saccharine sodium 2H2O, Dimeticon 350, highlydispersed silica, macrogol stearate 400, sorbic acid, flavoring agents.

[0011] Tablets with 1000 mg of Ca2+: 4954 mg of calcium lactogluconate,900 mg of calcium carbonate, and further constituents: citric acid,sodium cyclamate, saccharine sodium, mannitol, macrogol 4000, sodiumhydrogencarbonate, flavoring agents.

[0012] In order to spare patients multiple applications, and also forcost reasons, a combination of calcium preparations having a high Ca²⁺content with dry plant extract having an anti-osteoporosis effect wouldbe desirable.

[0013] Simple admixture to a calcium effervescent tablet mass, however,is foiled by the high sensitivity of the dry extracts to acids in anaqueous medium on the one hand, and by the poor water solubility of manydry extracts in an acidic medium on the other hand. Moreover thehumidity-sensitive effervescent masses are imperiled by the highlyhygroscopic dry extracts.

[0014] Encapsulation in customary gelatin capsules must equally be ruledout as the capsules are generally not water vapor tight and thus woulddecompose and/or agglomerate the dry plant extract, so that thepharmaceutical quality would cease to be ensured due to undefinedbioavailability, release, and/or effectivity. Moreover the stability ofsuch gelatin capsules is not warranted, for it is reported inliterature, e.g., that instances of crosslinking with the gelatin occurwhen plant extracts are encapsulated in gelatin, and significant changesof the ingredients result from water absorption by the dry extract.

[0015] Thus, for example, a sugar-coated tablet, or dragée, formulationconsisting of a mixture of calcium and dry plant extract would beoptimal. As was mentioned above, significant calcium contents of 500 mgCa²⁺ and more, together with the relatively large amounts of auxiliariesfor dragée manufacture, would result in large dragée sizes and weightswhich would not be acceptable to patients.

[0016] Known solid formulations are combination preparations of calciumwith vitamin D3 in the form of chewing tablets, e.g. as Ossofortin®forte chewing tablets by the company Strathmann AG+Co., Sellhopsweg 1,D-22459 Hamburg.

[0017] Such chewing tablets for supportive treatment of osteoporosishave the following composition:

[0018] 1500.3 mg of calcium carbonate (corresponding to 600 mg of Ca++),Colecalciferol dry concentrate (100 000 I.U./g) 400 I.U., furtherconstituents: xylitol, corn starch, saccharine sodium, flavoring agent,magnesium stearate.

[0019] Up to the present, no prior art has taught the combination ofcalcium preparations with plant extracts suited for the above describedprophylaxis and/or therapy of osteoporosis, for the above named reasons.

SUMMARY OF THE INVENTION

[0020] Accordingly it is an object of the present invention to furnish apharmaceutical formulation combining both the advantages of calciumsubstitution and—where necessary—vitamin D₃ substitution, and theadvantages of a dry plant extract for the prophylaxis and/or treatmentof osteoporosis.

[0021] This object is attained through the characterizing features ofclaim 1. As regards use, the object is attained through the features ofclaim 14, and in terms of method through the characterizing features ofclaim 16.

[0022] The invention in particular concerns a pharmaceutical formulationof a calcium salt and a dry plant extract, wherein the pharmaceuticalformulation includes an inner pressed body of at least one dry plantextract enveloped by at least one coating of at least one calcium salt.

[0023] Through the pharmaceutical formulation of the invention it ispossible for the first time to furnish combinations that are sensible interms of quantities, of dry plant extracts effective againstosteoporosis, such as, for example, Cimicifuga racemosa, Belamcandachinensis, Vitex agnus castus or Urtica dioica radix, and theirmixtures, with calcium. Here it is particularly advantageous that thecoating—other than customary in the prior art—consists of auxiliaries,but essentially contains active agent, i.e, calcium, exclusively.

DETAILED DESCRIPTION

[0024] For the manufacture of the dry plant extracts, the presentapplicant's PCT application WO 99/47149 is incorporated in its entiretyby reference. In addition to the solvents mentioned there, however, itis furthermore possible to extract the plants in question with mixturesof organic-aqueous solvents, exclusively aqueous, or also with the aidof supercritical CO₂ (e.g. in the case of Serenoa repens).

[0025] By the present pharmaceutical formulation it is achieved that thegenerally highly hygroscopic plant extracts usually formulated byaddition of water-binding auxiliaries e.g. to dragées or film tablets,may be made available with a low mass and small volume, embedded in acoat of an inert active principle having a protective effect againsthumidity in the form of a calcium salt.

[0026] As a result, an extremely favorable ratio of dry plant extract tocalcium to auxiliaries is obtained, so that it is partly even possibleto entirely omit auxiliaries, with the exception of small amounts oflubricants.

[0027] Thus it is for the first time possible to furnish a combinationpreparation of a dry plant extract, calcium salts and—wherenecessary—also vitamin D₃, which has a calcium content whereby theapproximately 1000 mg of Ca²⁺ ions p.d. required for prophylaxis and/ortherapy may be achieved without administration of additional calciumpreparations.

[0028] A preferred embodiment of the present invention is characterizedin that in the calcium-containing coating and/or in the inner dry plantextract pressed body it additionally contains cholecalciferols, inparticular Colecalciferol (vitamin D3).

[0029] Moreover the pharmaceutical formulation may in addition containat least one fluoride salt, in particular sodium fluoride, wherein it ispreferred for the fluoride salt to be present in the inner pressed body.

[0030] Preferably the pharmaceutical formulation is characterized inthat the dry plant extract is selected from the group consisting ofextracts from: Vitex agnus castus (chaste tree); Belamcanda chinensis(leopard lily/blackberry lily); Cimicifuga racemosa (black cohosh);Trifolium pratense L. (purple trefoil); Oenothera biennis hom.(primrose); Glycine soja (soy bean); Serenoa repens (saw-palmetto);Urtica dioica (stinging nettle), in particular its root; Cucurbita pepo(pumpkin), in particular its seed; Pygeum africanum; as well as suitablemixtures of these.

[0031] In a preferred embodiment of the pharmaceutical formulation ofthe invention, the calcium salt is selected from the group consisting ofcalcium carbonates; calcium hydrogen carbonates; calcium halides, inparticular calcium chlorides and calcium iodides; calcium phosphates;calcium hydrogen phosphates, in particular calcium monohydrogenphosphate; dicalcium hydrogen phosphates, calcium lactates; calciumlactonates; calcium succinates; calcium tartrates; calcium gluconates;others; as well as suitable mixtures of the above.

[0032] The preferred pharmaceutical formulation in accordance with thepresent invention is a coated tablet, wherein the coating is a pressedbody of at least one calcium salt, and the core is a pressed body of atleast one of the named dry plant extracts, wherein vitamin D₃ may inaddition be contained in the core.

[0033] The pharmaceutical formulation may, however, also be a dot tablet(bull-eye tablet) in which the core, although still entirely envelopedby the coating, nevertheless need not be centered inside the coating.

[0034] It is furthermore possible in the present pharmaceuticalformulation to form the coating of a plurality of calcium layers,wherein preferably each layer contains a different calcium salt.

[0035] A preferred pharmaceutical formulation has, e.g., a calciumcontent of approx. 50 to 1000 mg per coated tablet and a dry plantextract content of approx. 0.5 to 100 mg. Hereby it is possible throughone to three administrations per day, which is agreeable for thepatient, to supply the entire recommended daily dose of Ca²⁺ ions ofapprox. 1000 mg of Ca²⁺ with simultaneous administration of the requiredphytoextracts having an anti-osteoporosis action and of vitamin D₃.

[0036] Moreover a preferred pharmaceutical formulation may have apolymer film as an external envelope, whereby the swallowing propertyand the esophageal sliding property may be improved. Moreover thepolymer film may prevent dust abrasion and the penetration of humidityinto the coating. Such a polymer envelope is, however, not essential.

[0037] The pharmaceutical formulation of the present invention requiresfew auxiliaries or even none at all. Where necessary, however, theauxiliaries customary in galenics, for example disintegrants, inparticular on the basis of starches and/or their derivatives; binders,in particular microcrystalline cellulose, gum arabic; lubricants, inparticular stearic acid and/or magnesium stearate; as well as slipagents, in particular polyethylene glycol, and the like may be used.

[0038] Preferably the pharmaceutical formulations of the invention aresuited as medicaments for the treatment of osteoporosis of variousgeneses, and in a particularly preferred manner for the prophylaxisand/or therapy of osteoporoses brought about by lack of sexual hormonein women and men of advanced age.

[0039] Manufacture of the pharmaceutical formulations of the inventiontakes place in accordance with the following principle:

[0040] Initially a pressed body core is produced from a dry plantextract, wherein the dry plant extract is selected from the groupconsisting of: Vitex agnus castus (chaste tree); Belamcanda chinensis(leopard lily); Cimicifuga racemosa (black cohosh); Trifolium pratenseL. (purple trefoil); Oenothera biennis hom. (primrose); Glycine soja(soy bean); Serenoa repens (saw-palmetto); Urtica dioica (stingingnettle), in particular its root; Cucurbita pepo (pumpkin), in particularits seed; Pygeum africanum; as well as suitable mixtures of these.

[0041] This core is transferred onto a first partial quantity of acoating mixture of at least one calcium salt, subsequently filling isperformed with a second partial quantity of the coating mixture; and theentire formulation of the core and the two partial quantities of calciumsalt-containing coating mixture is pressed to form the pharmaceuticalformulation. The calcium salt is selected from the group consisting of:

[0042] calcium carbonates; calcium hydrogen carbonates; calcium halides,in particular calcium chlorides and calcium iodides; calcium phosphates;calcium hydrogen phosphates, in particular calcium monohydrogenphosphate; dicalcium hydrogen phosphates, calcium lactates; calciumlactonates; calcium succinates; calcium tartrates; calcium gluconates;others; as well as suitable mixtures of these.

[0043] Preferably the core is substantially centered on the firstpartial quantity of the coating mixture, whereby a so-called coatedtablet is obtained. It is, however, also possible to manufactureso-called bull-eye-tablets (dot tablets) having a core which is notcentered, however enveloped, and in which the core may be partly visiblethrough the coating.

[0044] For pressing tablets, commercially available tablet presses maybe used, such as those of the companies FETTE, KORSCH and KILIAN.Particularly suited, for example, is a synchronously operatingdouble-sided rotary press by the company MANESTY. In the double-sidedrotary press, the cores are produced on the one tower of the rotarypress and transferred by the intermediate transferring and centeringmechanism to the tower of the second rotary press, wherepress-application of the coating takes place.

[0045] More basically, the pharmaceutical formulations of the presentinvention may, however, also be carried out with two rotary presses,where the cores are pressed in one of them, while press-application ofthe coating takes place in the second one.

[0046] The advantage for the manufacture of the coated tablets of theinvention as a pharmaceutical formulation with the aid of a double-sidedrotary press, however, resides in the fact that the cores may bepre-pressed in the first tower of the press so as to be comparativelysoft. Final compression in the second tower of the double-sided rotarypress thus results in very good adhesion between dry plant extract coreand calcium coating.

[0047] A coated tablet manufactured in this manner has, for example, thefollowing composition: Coating: CaCO₃ 1250 mg (corr. to 500 mg ofvitamin D₃ Ca²⁺) 200 I.U. Core: Cimicifuga racemosa  20 mg (dry extractpreparation) Auxiliaries: magnesium stearate   8 mg stearic acid   4 mgmicrocrystalline cellulose  40 mg gum arabic  50 mg

[0048] The exemplary coated tablet combines the advantages of oralcalcium and vitamin D₃ substitution with the required dose of Cimicifugaracemosa dry extract. By oral application of no more than 2 tabletsdaily, the dose recommended for the prophylaxis and/or therapy ofosteoporosis of calcium and vitamin D₃ dose of approx. 1000 mg of Ca²⁺p.d., or 400 I.U. of vitamin D₃, as well as the desired simultaneousadministration of 40 mg of Cimicifuga racemosa dry extract is achieved.

[0049] It is, of course, also possible and advantageous to manufacturethe dry extract core from other of the named phyto-extracts or frommixtures of different extracts depending on the constellation ofindications. Thus, e.g., a coated tablet of the invention, adjusted forailments of the prostate, may contain a Serenoa repens extract in thecore.

1. Pharmaceutical formulation of a calcium salt and a dry plant extract,characterized in that the pharmaceutical formulation includes an innerpressed body of at least one dry plant extract, which is enveloped by atleast one calcium-containing coating.
 2. Pharmaceutical formulation inaccordance with claim 1, characterized in that the dry plant extract isselected from the group consisting of extracts from: Vitex agnus castus(chaste tree); Belamcanda chinensis (leopard lily); Cimicifuga racemosa(black cohosh); Trifolium pratense L. (purple trefoil); Oenotherabiennis hom. (primrose); Glycine soja (soy bean); Serenoa repens(saw-palmetto); Urtica dioica (stinging nettle), in particular its root;Cucurbita pepo (pumpkin), in particular its seed; Pygeum africanum; aswell as suitable mixtures of these.
 3. Pharmaceutical formulation inaccordance with claim 1 or 2, characterized in that the calcium salt isselected from the group consisting of: calcium carbonates; calciumhydrogen carbonates; calcium halides, in particular calcium chloridesand calcium iodides; calcium phosphates; calcium hydrogen phosphates, inparticular calcium monohydrogen phosphate; dicalcium hydrogenphosphates, calcium lactates; calcium lactonates; calcium succinates;calcium tartrates; calcium gluconates; as well as suitable mixtures ofthese.
 4. Pharmaceutical formulation in accordance with any one ofclaims 1 to 3, characterized in that it is a coated tablet, wherein thecoating is a pressed body of at least one calcium salt, and the core isa pressed body of at least one dry plant extract.
 5. Pharmaceuticalformulation in accordance with any one of claims 1 to 4, characterizedin that it is a dot tablet (bull-eye tablet).
 6. Pharmaceuticalformulation in accordance with any one of claims 1 to 5, characterizedin that the coating includes a plurality of calcium layers, whereinpreferably each layer contains a different calcium salt. 7.Pharmaceutical formulation in accordance with any one of claims 1 to 6,characterized in that it has a calcium content of approx. 50 to 1000 mgper coated tablet and a dry plant extract content of approx. 0.5 to 100mg.
 8. Pharmaceutical formulation in accordance with any one of claims 1to 7, characterized in that it additionally has a polymer film as anexternal envelope.
 9. Pharmaceutical formulation in accordance with anyone of claims 1 to 8, characterized in that it has a calcium content ofapprox. 1250 mg of calcium carbonate (corresponding to approx. 500 mg ofCa²⁺) and approx. 200 I.U. vitamin D₃ in the coating of the coatedtablet as well as approx. 20 mg dry extract preparation of Cimicifugaracemosa in the core of the coated tablet.
 10. Pharmaceuticalformulation in accordance with any one of claims 1 to 9, characterizedin that in the calcium-containing coating and/or in the inner pressedbody of dry plant extract it additionally contains cholecalciferoles, inparticular Colecalciferol (vitamin D₃).
 11. Pharmaceutical formulationin accordance with any one of claims 1 to 10, characterized in that itadditionally contains at least one fluoride salt, in particular sodiumfluoride.
 12. Pharmaceutical formulation in accordance with claim 11,characterized in that the fluoride salt is present in the inner pressedbody.
 13. Pharmaceutical formulation in accordance with any one ofclaims 1 to 12, characterized in that by way of auxiliaries it includesdisintegrants, in particular on the basis of starches and/or theirerivatives; binders, in particular microcrystalline cellulose, gumarabic; lubricants, in particular stearic acid and/or magnesiumstearate; as well as slip agents, in particular polyethylene glycol. 14.Use of the pharmaceutical formulation in accordance with any one ofclaims 1 to 13 as a medicament for the treatment of osteoporoses ofvarious geneses.
 15. Use in accordance with claim 14, characterized inthat the pharmaceutical formulation is used as a medicament for thetreatment of osteoporoses brought about by lack of sexual hormone, forthe prevention and treatment of hormone-related geriatric complaints, inparticular menopausal complaints, prostate afflictions; and accompanyingcardiovascular disorders, as well as disturbances of the metabolism oflipids, and in particular disorders accompanying calcium deficiency. 16.Method for manufacturing a pharmaceutical formulation in accordance withany one of claims 1 to 4 and 6 to 13, characterized in that a pressedbody core is manufactured of a dry plant extract, wherein the dry plantextract is selected from the group consisting of extracts from: Vitexagnus castus (chaste tree); Belamcanda chinensis (leopard lily);Cimicifuga racemosa (black cohosh); Trifolium pratense L. (purpletrefoil); Oenothera biennis hom. (primrose); Glycine soja (soy bean);Serenoa repens (saw-palmetto); Urtica dioica (stinging nettle), inparticular its root; Cucurbita pepo (pumpkin), in particular its seed;Pygeum africanum; as well as suitable mixtures of these; the core istransferred to a first partial quantity of a coating mixture of at leastone calcium salt, which is followed by filling with a second partialquantity of the coating mixture; and the entire formulation comprised ofthe core and the two partial quantities of the calcium salt-containingcoating mixture is pressed to form the pharmaceutical formulation;wherein the calcium salt is selected from the group consisting of:calcium carbonates; calcium hydrogen carbonates; calcium halides, inparticular calcium chlorides and calcium iodides; calcium phosphates;calcium hydrogen phosphates, in particular calcium monohydrogenphosphate; dicalcium hydrogen phosphates, calcium lactates; calciumlactonates; calcium succinates; calcium tartrates; calcium gluconates;as well as suitable mixtures of these.
 17. Method in accordance withclaim 16, characterized in that the core is centered on the firstpartial quantity of the coating mixture.
 18. Method in accordance withclaim 16 or 17, characterized in that auxiliaries used aredisintegrants, in particular on the basis of starches and/or theirderivatives; binders, in particular microcrystalline cellulose, gumarabic; lubricants, in particular stearic acid and/or magnesiumstearate; as well as slip agents, in particular polyethylene glycol.